Treatment of epileptic disorders in feline animals

ABSTRACT

A method for treatment and/or prevention of one or more epileptic disorders in a feline animal, preferably a cat, includes administration of 1-(4-chlorophenyl)-4-(4-morpholinyl)-2.5-dihydro-1H-imidazol-2-one or a physiologically acceptable salt thereof to the feline animal.

FIELD OF THE INVENTION

The present invention relates to veterinary medicine, in particular tothe treatment and/or prevention of epileptic disorders in felineanimals.

BACKGROUND OF THE INVENTION

Clinical characteristics and treatment with antiepileptic drugs (AEDs)in cats is fundamentally different from dogs and other species.Treatment options are limited, and only limited data are available(Platt 2001). The “International League Against Epilepsy” (ILAE) gradesstudies for human treatment in four categories of study quality, fromclass I for well controlled, randomized, double-blind trials with largenumbers of cases to class IV for expert opinions and anecdotal casereports. Knowledge on epilepsy treatment in cats can be regarded aslowest grade of evidence (class IV).

Accordingly it is very difficult for a person skilled in the art tochoose an appropriate treatment option for cats. In addition, there is asufficient body of evidence proving that cats react different to mostAEDs compared to dogs and other species (Pakozdy et al. 2014). Many AEDshave unfavorable pharmacokinetic properties, low or unproven efficacy oreven toxic effects in cats, limiting their potential use as describedbelow in detail.

Oral diazepam has a longer elimination half-life in cats (15-20 h) thanin dogs (3-4 h) and cats do not develop functional tolerance to the drugin contrast to other species, including rat, mouse, dog and human.Beside non-fatal adverse events like sedation, polyuria and polydipsia,it has been linked to potentially fatal idiosyncratic hepatotoxicosis,hepatic necrosis and liver failure. Consequently oral diazepam isconsidered contraindicated in cats (Smith Bailey 2009). This situationis similar to other benzodiazepines, like clorazepate. In terms ofefficacy, full benzodiazepine agonists are regarded as very efficacioustreatment, but not used due to the possible life-threatening sideeffects.

Bromide is neither considered sufficiently effective, as seizures areonly controlled in about 35% of treated cats, and bromide is associatedwith severe side effects in cats, especially an idiosyncratic allergicpneumonitis occurring in 35-42% of treated cats. As this adverse eventis potentially life-threatening, also bromide is, in contrast to dogs,not a therapeutic option in cats (Boothe et al. 2002).

Phenobarbital is the current treatment of choice, based on its lowprice, relatively long elimination time, long history of chronic use andacceptable tolerability. However the safety profile and pharmacokineticsare different from dogs and other species. In contrast to dogs, it isnot linked to hepatopathy and development of drug tolerance. In cats,sedation, ataxia, polyuria, polydipsia, leukopenia, thrombocytopenia,lymphadenopathies, skin eruptions and coagulopathies have been describedas adverse events. In a recent study, sedation was reported in over 40%of all treated cases, and even resulting in two fatal events (one catwas euthanized, as phenobarbital did not control seizures but led tosevere sedation, another cat had a fatal accident due to severesedation) (Pakozdy et al. 2013). In addition, phenobarbital has a strongaddictive effect. It is effective in many cases; however there seems tobe still a quite high rate of poor responding epileptic cats (ca. 30%).

Approximately half of healthy cats receiving a 20 mg/kg dose ofzonisamide experience adverse reactions such as anorexia, diarrhea,vomiting, somnolence and ataxia, and sufficient efficacy has not beenconvincingly demonstrated.

Levetiracetam was shown in one study to be somewhat effective as add-ontherapy in cats with refractory epilepsy under phenobarbital treatment,however in only 10 cats and in a study with methodological weaknesses.Sedation, inappetence and hypersalivation were attributed side-effects.Other drugs were only anecdotally used in cats, and there are no datasupporting their routine use in clinical practice (Pakozdy et al. 2014).

Barnes H L et al. (JAVMA 2004, 225(11): 1723-1726) discuss clinicalsigns, underlying cause, and outcome in 17 cats with seizures.

Fromm G H et al. (Fromm et al. 1985) compared the effect of theexperimental antiepileptic gamma-aminobutyric acid (GABA) agonist drugprogabide on the trigeminal complex of cats with the effect ofestablished antiepileptic drugs and with the effect of various GABAagonists and antagonists. Their experiments indicated that progabide,but not THIP or muscimol, should have antiepileptic properties. However,the reason for the differential effect of the three GABA agonistsremained to be elucidated.

Morimoto K and co-workers (Morimoto K et al. 1993) conducted acomparative study of the anticonvulsant effect of GABA agonists onfeline amygdala or hippocampal kindled seizures. They showed thatprogabide, SKF89976A and gamma-vinyl GABA have potent anticonvulsanteffects on partial onset and secondarily generalized limbic seizures.Selective GABAB receptor agonist baclofen, however, did not showanticonvulsant effects on any parameters of kindled seizures.

Quesnel A D et al. (JAVMA 1997, 210(1): 72-77) discuss the clinicalmanagement and outcome of cats with seizure disorders in 30 cases.

Schwartz-Porsche D et al. (Feline Epilepsy. In: Inderi R J ed. Problemsin Veterinary Medicine. Vol. 1, No. 4, Philadelphia, Pa., Lippincott,1989: 628-649) gives a review on feline epilepsy.

WO 2013/024023 discloses taste masked pharmaceutical compositions.

In summary, AEDs in cats show an adverse event profile which issignificantly different from dogs. Development of drug tolerance, whichis common for phenobarbital and benzodiazepines in dogs, humans androdents, seem to play a minor role in cats. Sedation is a common sideeffect in all antiepileptic drugs used in the cat, as mentioned above.This can be regarded as relevantly reduced quality of life for thediseased cat, and it also is a disadvantage for the owner-catinteraction.

The objective underlying the present invention is therefore to provide amedication for preventing and/or treating epileptic disorders in felineanimals, which overcomes the problems and limitations of the prior art.

SUMMARY OF THE INVENTION

In one aspect, the objective of the present invention has surprisinglybeen solved by providing1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one(imepitoin) or a physiologically acceptable salt thereof for use in amethod for treatment and/or prevention of one or more epilepticdisorders in a feline animal.

Corresponding methods of prevention and/or treatment of one or moreepileptic disorders in a feline animal in need thereof and uses for thepreparation of a pharmaceutical composition/medicament for theprevention and/or treatment of one or more epileptic disorders in afeline animal are also intended to be within the scope of the presentinvention.

Imepitoin (AWD 131-138 or ELB 138;1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one) is anew chemical entity that was presented at the EILAT IV, V and

XI conferences on new antiepileptic drugs (AEDs) (Bialer et al., 1999,2001, 2013).

It was developed in the 1990s from a series of imidazolinones.Furthermore, it was tested in the NINDS-sponsored AnticonvulsantScreening Project (ASP). Imepitoin was selected for further developmentbecause of its broad spectrum of anticonvulsant activity, hightherapeutic index, and its efficacy in tests predictive for anxiolyticeffects. It underwent Phase I clinical studies, but further clinicaldevelopment for humans was suspended. However, interesting findings indogs led to the decision to develop imepitoin as a new AED for canineepilepsy. There is a wide range of literature discussing theanticonvulsant efficacy of imepitoin in rodents, dogs and primates(Löscher W et al., 2004; Rieck S et al., 2006; Löscher W et al., 2013;Penderis J et al., 2013; Rundfeldt C et al., 2014; WO 2004/032938).

In another aspect, the objective of the present invention hassurprisingly been solved by providing1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one(imepitoin) or a physiologically acceptable salt thereof for the uses asherein described in a method for prevention of one or more epilepticdisorders in a feline animal.

In another aspect, the objective of the present invention hassurprisingly been solved by providing1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one(imepitoin) or a physiologically acceptable salt thereof for the uses asherein described, wherein the one or more epileptic disorders isselected from the group consisting of: idiopathic (primary, genetic)epilepsy, symptomatic (secondary, structural/metabolic) epilepsy,cryptogenic (of unknown cause, probable symptomatic) epilepsy, reactiveepileptic seizures; preferably is idiopathic (primary, genetic) epilepsyand symptomatic (secondary, structural/metabolic) epilepsy andcryptogenic (of unknown cause, probable symptomatic) epilepsy, morepreferably is idiopathic (primary, genetic) epilepsy.

In this context and in the course of the present invention, terms“idiopathic epilepsy”, “primary epilepsy” and “genetic epilepsy” areused interchangeably. The same holds true for terms “symptomaticepilepsy”, “secondary epilepsy” and “structural/metabolic epilepsy”,which are also used interchangeably. Finally, terms “probablesymptomatic epilepsy”, “cryptogenic epilepsy” and “epilepsy of unknowncause” are also used interchangeably.

In yet another aspect, the objective of the present invention hassurprisingly been solved by providing1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof for the uses as hereindescribed, wherein1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof is to be administered incombination with one or more further antiepileptic drugs, preferably inform of a simultaneous, a sequential and/or a chronologically staggeredco-administration, more preferably in a simultaneous co-administration.

Preferably, such one or more further antiepileptic drug is selected fromthe group consisting of: phenobarbital, diazepam, potassium bromide,clorazepate, levetiracetam, gabapentin, zonisamide, pregabalin,propentophyllin, taurine, topiramate.

More preferably, the feline animal has first been treated with one ormore further antiepileptic drug selected from the group consisting of:phenobarbital, diazepam, potassium bromide, clorazepate, levetiracetam,gabapentin, zonisamide, pregabalin, propentophyllin, taurine,topiramate, preferably with phenobarbital, before the treatment isswitched to1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof.

In yet another aspect, the objective of the present invention hassurprisingly been solved by providing1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof for the uses as hereindescribed, wherein1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof is to be administered in form ofa monotherapy, i.e. not in combination with one or more furtherantiepileptic drugs, such as the ones disclosed herein, in particularphenobarbital, such as a simultaneous, a sequential and/or achronologically staggered co-administration.

For the avoidance of doubt, in this context “monotherapy” refers to thetreatment with antiepileptic drugs only. That is no other antiepilepticdrug is given to the feline animal in the course of such monotherapeuticantiepileptic treatment. However, it may be the case and/or evenpreferred that one or more other drugs, i.e. non-antiepileptic drugs,are co-administered to the feline animal, e.g. in a simultaneous, asequential and/or a chronologically staggered co-administration, inorder to treat and/or prevent one or more other diseases not being oneor more epileptic disorders.

In yet another aspect, the objective of the present invention hassurprisingly been solved by providing1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof for the uses as hereindescribed, wherein the one or more epileptic disorders are antiepilepticdrug resistant or -refractory epileptic disorders, preferablyphenobarbital-resistant or -refractory epileptic disorders, morepreferably phenobarbital-resistant or -refractory idiopathic (primary,genetic) epilepsy and phenobarbital-resistant or -refractory symptomatic(secondary, structural/metabolic) epilepsy and phenobarbital-resistantor -refractory probable symptomatic (cryptogenic, of unknown cause)epilepsy, most preferably phenobarbital-resistant or -refractoryidiopathic (primary, genetic) epilepsy.

In yet another aspect, the objective of the present invention hassurprisingly been solved by providing1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof for the uses as hereindescribed, wherein1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof is to be administered once,twice or three-times daily, preferably once or twice per day, morepreferably twice per day.

In yet another aspect, the objective of the present invention hassurprisingly been solved by providing1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof for the uses as hereindescribed, wherein1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof is to be administered at a doseof from 1 to 150 mg/kg bodyweight, preferably from 5 to 100 mg/kgbodyweight, more preferably from 5 to 50 mg/kg bodyweight, even morepreferably from 20 to 100 mg/kg bodyweight, even more preferably from 20to 60 mg/kg bodyweight, most preferably 25 to 40 mg/kg bodyweight, andwherein such dose preferably is to be administered once, twice orthree-times per day, more preferably once or twice per day, mostpreferably twice per day.

In yet another aspect, the objective of the present invention hassurprisingly been solved by providing1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof for the uses as hereindescribed, wherein the dose to be administered is from 20 to 60 mg/kgbodyweight, preferably from 25 to 40 mg/kg bodyweight, and whereinpreferably such dose is to be administered twice per day.

In yet another aspect, the objective of the present invention hassurprisingly been solved by providing1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof for the uses as hereindescribed, wherein1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof is to be administered orally orparenterally, preferably orally.

In yet another aspect, the objective of the present invention hassurprisingly been solved by providing1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof for the uses as hereindescribed, wherein the feline animal is a cat.

In yet another aspect, the objective of the present invention hassurprisingly been solved by providing a pharmaceutical compositioncomprising1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof for the uses as hereindescribed. In contrast to other feline antiepileptic drug medications,imepitoin advantageously causes no sedation or other considerable sideeffects in feline animals, even when administered at higher doses, forinstance from 20 to 60 mg/kg bodyweight, preferably 25 to 40 mg/kgbodyweight, such as 20 to 60 mg/kg bodyweight, preferably 25 to 40 mg/kgbodyweight once, twice or three-times per day.

Moreover, in view of its mode of action, being a partial agonist at thebenzodiazepine binding site, one might expect similar, potentially fatalside effects for imepitoin as for other benzodiazepines. However,surprisingly imepitoin does not cause any toxic effects on liver norother benzodiazepine-like adverse events.

Furthermore and unexpectedly, imepitoin is highly effective incontrolling epileptic seizures in cats. Cats with uncontrolled orcontinuing seizures under phenobarbital treatment became seizure freeafter transition to imepitoin monotherapeutic treatment, which issuperior to the limited levetiracetam data, where only add-on therapywas effective. This is in strong contrast to the situation in dogs,where imepitoin has only a comparable efficacy to phenobarbital, and isnot regarded as a replacement for refractory phenobarbital cases, i.e.patients which suffer from phenobarbital resistant or -refractoryepileptic disorders.

In yet another aspect, the objective of the present invention hassurprisingly been solved by providing1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof for the uses as hereindescribed, wherein the feline animal has uncontrolled or continuingseizures under treatment with one or more further antiepileptic drugselected from the group consisting of: phenobarbital, diazepam,potassium bromide, clorazepate, levetiracetam, gabapentin, zonisamide,pregabalin, propentophyllin, taurine, topiramate, preferably undertreatment with phenobarbital.

In yet another aspect, the objective of the present invention hassurprisingly been solved by providing1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof for the uses as hereindescribed, wherein the administration of1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one(imepitoin) or a physiologically acceptable salt thereof leads tocomplete prevention of seizures (seizure freedom), preferably at dosesof 15 mg/kg bodyweight or higher, more preferably at doses of 20 to 60mg/kg bodyweight, more preferably at doses of 25 to 40 mg/kg bodyweight,even more preferably 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg,40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg or 60 mg/kg bodyweight, even morepreferably 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg,50 mg/kg, 55 mg/kg or 60 mg/kg bodyweight, most preferably 25 mg/kg, 30mg/kg, 35 mg/kg or 40 mg/kg bodyweight.

In yet another aspect, the objective of the present invention hassurprisingly been solved by providing1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof for the uses as hereindescribed, wherein a high initial/starting dose of1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one(imepitoin) or a physiologically acceptable salt thereof is reducedduring the course of treatment while maintaining effective controland/or prevention of seizures, preferably moderate or good seizurecontrol, more preferably complete prevention of seizures (seizurefreedom). Preferred initial/starting doses are 15 mg/kg bodyweight orhigher, more preferably doses of 20 to 60 mg/kg bodyweight, morepreferably doses of 25 to 40 mg/kg bodyweight, even more preferably 15mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50mg/kg, 55 mg/kg or 60 mg/kg bodyweight, even more preferably 20 mg/kg,25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg or60 mg/kg bodyweight, most preferably 25 mg/kg, 30 mg/kg, 35 mg/kg or 40mg/kg bodyweight. The initial/starting dose can be reduced after initialtreatment to lower maintenance doses of 0.5 to 60 mg/kg body weight,preferably from 1 to 30 mg/kg bodyweight, more preferably from 5 to 20mg/kg bodyweight, even more preferably 1 mg/kg, 2 mg/kg, 5 mg/kg, 8mg/kg, 10 mg/kg, 12.5 mg/kg, 15 mg/kg, 18 mg/kg, 20 mg/kg, 25 mg/kg or30 mg/kg bodyweight, most preferably 5 mg/kg, 10 mg/kg, 15 mg/kg or 20mg/kg bodyweight. Preferably such doses are to be administered once,twice or three-times per day, more preferably once or twice per day,most preferably twice per day. The initial/starting dose should behigher than the lower maintenance dose. The switch from theinitial/starting dose (initial treatment) to the lower maintenance dosecan be performed at any time of treatment starting one day aftertreatment initiation, preferably between two days and nine months aftertreatment initiation, more preferably between three days and six monthsafter treatment initiation, most preferably between three days and threemonths after treatment initiation.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 Mean plasma concentration-time curves of imepitoin after thefirst oral dose of 30 mg/kg imepitoin in male (M) and female cats (F) atDay 0, Day 14 and Day 29 (semi-logarithmic scale).

FIGS. 2A and 2B Results of clinical chemistry for enzymes in blood,routinely used to judge liver function and diagnose liver pathologies(FIG. 2A=untreated/control; FIG. 2B=imepitoin at 30 mg/kg bodyweighttwice daily).

FIG. 3 Measurement of Alkaline Phosphatase (AP) in serum followingadministration of imepitoin in doses of 40 or 80 mg/kg bodyweight twicedaily, or placebo. AP is routinely used to judge liver function anddiagnose liver pathologies, and an elevated AP is indicative for avariety of diseases. All values measured here are in the physiologicalrange with normal variance. Day 0 reflects measurement before treatmentstart.

DETAILED DESCRIPTION OF THE INVENTION

Before the embodiments of the present invention are described in furtherdetails it shall be noted that as used herein and in the appendedclaims, the singular forms “a”, “an”, and “the” include plural referenceunless the context clearly dictates otherwise.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs. All given ranges and valuesmay vary by 1 to 5% unless indicated otherwise or known otherwise by theperson skilled in the art, therefore, the term “about” was usuallyomitted from the description and claims. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methods,devices, and materials are now described. All publications mentionedherein are incorporated herein by reference for the purpose ofdescribing and disclosing the substances, excipients, carriers, andmethodologies as reported in the publications which might be used inconnection with the invention. Nothing herein is to be construed as anadmission that the invention is not entitled to antedate such disclosureby virtue of prior invention.

In the following,1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one(imepitoin) is also referred to as compound of the (present) invention.

The compound of the invention can, if it has a sufficiently basic groupsuch as, for example, a secondary or tertiary amine, be converted withinorganic and organic acids into salts. The pharmaceutically acceptablesalts of the compound of the invention are preferably formed withhydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid,phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonicacid, formic acid, acetic acid, sulfoacetic acid, trifluoroacetic acid,oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid,racemic acid, malic acid, embonic acid, mandelic acid, fumaric acid,lactic acid, citric acid, taurocholic acid, glutaric acid, stearic acid,glutamic acid or aspartic acid. The salts which are formed are, interalia, hydrochlorides, chlorides, hydrobromides, bromides, iodides,sulfates, phosphates, methanesulfonates, tosylates, carbonates,bicarbonates, formates, acetates, sulfoacetates, triflates, oxalates,malonates, maleates, succinates, tartrates, malates, embonates,mandelates, fumarates, lactates, citrates, glutarates, stearates,aspartates and glutamates. The stoichiometry of the salts formed fromthe compound of the invention may moreover be an integral ornon-integral multiple of one.

The compound of the invention can, if it contains a sufficiently acidicgroup such as, for example, the carboxy, sulfonic acid, phosphoric acidor a phenolic group, be converted with inorganic and organic bases intoits physiologically tolerated salts. Examples of suitable inorganicbases are ammonium, sodium hydroxide, potassium hydroxide, calciumhydroxide, and of organic bases are ethanolamine, diethanolamine,triethanolamine, ethylenediamine, t-butylamine, t-octylamine,dehydroabietylamine, cyclohexylamine, dibenzylethylene-diamine andlysine. The stoichiometry of the salts formed from the compound of theinvention can moreover be an integral or non-integral multiple of one.

It is likewise possible for the compound of the invention to be in theform of its solvates and, in particular, hydrates which can be obtainedfor example by crystallization from a solvent or from aqueous solution.It is moreover possible for one, two, three or any number of solvate orwater molecules to combine with the compound of the invention to givesolvates and hydrates. By the term “solvate” is meant a hydrate, analcoholate, or other solvate of crystallization.

In the course of the present invention, (antiepileptic) drug resistantor -refractory epileptic disorders, preferably phenobarbital-resistantor -refractory epileptic disorders, refers to failure of adequate trialsof one or two tolerated and appropriately chosen and used anti-epilepticdrug (AED) schedules (whether as monotherapies or in combination) toachieve sustained therapeutic success (e.g. seizure freedom orsignificant reduction in seizure frequency).

Feline Animals

Herein, a feline animal is a member of the Felidae family (i.e. afelid). It may thus belong either to the subfamily felinae or thesubfamily pantherinae. The term feline animal encompasses the term cat,e.g., a domestic cat. The term domestic cat encompasses the terms Feliscatus and Felis silvestris catus.

Dosage

The dosage regimen for the compound of the present invention accordingto the present invention will, of course, vary depending upon knownfactors, such as the pharmacodynamic characteristics of the particularagent and its mode and route of administration; the species, age, sex,health, medical condition, and weight of the recipient; the nature andextent of the symptoms; the kind of concurrent treatment; the frequencyof treatment; the route of administration, the renal and hepaticfunction of the patient, and the effect desired.

A physician or veterinarian can determine and prescribe the effectiveamount of the drug required to prevent, counter, or arrest the progressof the disorder.

In addition, radioisotope labeled compound of the invention (e.g.^(99m)Tc) can be used to examine the distribution of the compound of theinvention and their potential metabolites in the body.

Based on the currently available scientific data, the dose of thecompounds of the invention, when used for the indicated effects, will bein the range of from 0.5 or 1 to 150 mg/kg bodyweight, preferably from 5to 100 mg/kg bodyweight, more preferably from 5 to 50 mg/kg bodyweight,even more preferably from 20 to 100 mg/kg bodyweight, even morepreferably from 20 to 60 mg/kg bodyweight, most preferably 25 to 40mg/kg bodyweight. Examples of individual doses are 1 mg/kg, 2 mg/kg, 5mg/kg, 8 mg/kg, 10 mg/kg, 12.5 mg/kg, 15 mg/kg, 18 mg/kg, 20 mg/kg, 22mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90mg/kg, 95 mg/kg, 100 mg/kg bodyweight, preferably 10 mg/kg, 15 mg/kg, 20mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55mg/kg or 60 mg/kg bodyweight, more preferably 20 mg/kg, 25 mg/kg, 30mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg or 60 mg/kgbodyweight, most preferably 25 mg/kg, 30 mg/kg, 35 mg/kg or 40 mg/kgbodyweight. These doses are preferably to be administered once, twice orthree-times per day, preferably once or twice daily/once or twice perday, more preferably twice per day. Also, if treated two or three timesa day, equal or different doses can be administered.

Alternatively, the dosage can be split into/reduced to anywhere inbetween one dose once in two days up to one dose once in a week. Thetreatment is advisable in clinically apparent cases, both in acute aswell as in chronic settings.

Administration

Suitable forms for administration are for example parenteral or oraladministration of the compound of the invention, preferably oraladministration.

The compound of the invention can be formulated for instance in a solid,preferably a tablet formulation, or a liquid formulation.

Efficacy

Efficacy is based on the proportion of animals that achieve seizurefreedom (complete prevention of seizures) over a given observationperiod, for example, 1 week, 2 weeks, 3 weeks, 4 weeks, 1 months, 2months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 11 months, 12 months, 13 months, 14 months, 15months, 16 months, 17 months, 18 months, 19 months, 20 months, 21months, 22 months, 23 months, 24 months, 1 year, 2 years, 3 years, 4years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years or evenlonger. Such seizure freedom can be achieved, preferably withoutconsiderable adverse events, at doses of for example 15 mg/kg bodyweightor higher, such as doses of 20 to 60 mg/kg bodyweight or doses of 25 to40 mg/kg bodyweight, for instance 15 mg/kg, 20 mg/kg, 25 mg/kg, 30mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg or 60 mg/kgbodyweight, preferably 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg,45 mg/kg, 50 mg/kg, 55 mg/kg or 60 mg/kg bodyweight, more preferably 25mg/kg, 30 mg/kg, 35 mg/kg or 40 mg/kg bodyweight of the compound of theinvention.

During the course of treatment, the initial/starting dose can be reducedto lower maintenance doses to achieve the indicated herein describedeffects. These lower maintenance doses are preferably in the range offrom 0.5 to 60 mg/kg bodyweight, more preferably from 1 to 30 mg/kgbodyweight, even more preferably from 5 to 20 mg/kg bodyweight. Examplesof individual doses are 1 mg/kg, 2 mg/kg, 5 mg/kg, 8 mg/kg, 10 mg/kg,12.5 mg/kg, 15 mg/kg, 18 mg/kg, 20 mg/kg, 22 mg/kg, 25 mg/kg, 30 mg/kgbodyweight, most preferably 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg or 25mg/kg bodyweight. These doses are also preferably to be administeredonce, twice or three-times per day, preferably once or twice daily/onceor twice per day, more preferably twice per day.

In this context and in the context of the present invention “seizurefreedom” (complete prevention of seizures) or “seizure-free” means thata given animal does not show one or more seizures in the respectiveobservation period, preferably in a year.

In the context of the present invention “good seizure control” or “goodcontrol of seizures” means that a given animal does only show 1 to 5seizures in the respective observation period, preferably in a year.

In the context of the present invention “moderate seizure control” or“moderate control of seizures” means that a given animal does only show6 to 10 seizures in the respective observation period, preferably in ayear.

In the context of the present invention “poor seizure control” or “poorcontrol of seizures” means that a given animal does only show more than10 seizures in the respective observation period, preferably in a year.

Considerable Adverse Events

The compound of the invention upon administration of the hereindescribed doses and dosage regimens to a feline animal advantageouslyand preferably does not cause/elicit considerable adverse events. Inthis context and in the context of the present invention “considerableadverse events” refers to severe sedation, severe and long lastingsomnolence (i.e. longer than 3 hours), hepatotoxicosis, hepaticnecrosis, liver failure, kidney damage, kidney failure, drug addiction,leukopenia, thrombocytopenia, lymphadenopathies, coagulopathies and/ordeath.

EXAMPLES

The following examples serve to further illustrate the presentinvention; but the same should not be construed as a limitation of thescope of the invention disclosed herein.

Example 1—Pharmacokinetics

When administered orally at a preferred dose of e.g. 30 mg/kg bodyweighttwice daily (60 mg/kg bodyweight daily dose) imepitoin the highestplasma concentration (t_(Max)) is reached in median 1 hour (range 0.5 to3 hours) after administration, in most cases 1 hour. This plasmaconcentration rapidly declines over the next 24 hours, with a half-lifetime t_(1/2) of 1.5 hours.

The highest C_(max)-values of imepitoin is observed at the first day ofdosing (Day 0), 1 to 3 hours after the first dose is given. Mean C_(max)values are 7050 ng/mL for males (n=3) and 6643 ng/mL for females (n=3).Corresponding AUC_(0-6h)-values are 28001 ng·h/mL and 24467 ng·h/mL,respectively. After 14 and 29 days of twice daily dosing, a slightlylower exposure of imepitoin is observed compared to the first dosingday, indicating that no accumulation occurs upon long-term BID dosing.

The last measurable concentration is found after more than 18 hoursindicating that a dosing interval of 12 hours (twice daily) is adequateto assure permanent plasma levels throughout a chronic treatment.

The imepitoin serum plasma concentration over time is shown in FIG. 1.

In conclusion, the pharmacokinetic data show a favorable profile foradministration in a feline animal.

Example 2—Safety 1

In a randomized, controlled, blinded study the tolerance of imepitoin isinvestigated in clinically healthy male and female cats after repeatedoral administration for 30 days.

Twelve 1-3 years old, male and female domestic short hair cats with abody weight range of 2.8-4.4 kg are assigned to this study. The animalsare randomly allocated to two groups, three male and three femaleanimals per group. The test article (imepitoin) is orally administeredto the animals of group II at a target dose of 30 mg imepitoin/kgbodyweight twice daily at an interval of 8-12 h on days 0-29. Group I isleft untreated serving as controls.

Mortality is not observed. No evidence of a clear effect of the repeatedadministration of imepitoin to cats on body weight development, food andwater consumption, heart rate, respiratory rate and on parameters oflaboratory investigations (i.e. hematology, clinical chemistry andurinalysis) is found. No sedation is observed in any animal.

With respect to the liver there is no difference betweenimepitoin-treated and untreated (control) animals as shown by liverenzyme measurements (FIGS. 2A+2B).

Temporary vomitus or choking is noted in 3 of 6 animals of the treatedgroup from the second week of treatment onwards. Two males of theuntreated control group also show a vomitus at one occasion. It isnoteworthy that vomitus is observed in cats from time to time after oraladministration irrespective of the administered substance.

In conclusion, imepitoin shows a favorable safety profile in felineanimals at preferred high doses.

Example 3—Safety 2

Eighteen 9 months old, male and female domestic short hair cats with abody weight range of 2.3-4.9 kg are assigned to this study. The animalsare allocated to three test groups employing a pseudo-random body weightstratification procedure that yielded groups with approximately equalmean body weight, with three male and three female animals per group.The test article (imepitoin) is orally administered to the animals at atarget dose of 40 mg imepitoin/kg bodyweight and 80 mg imepitoin/kgbodyweight twice daily at an interval of 8-12 h on days 0-30. The thirdgroup receives visually identical placebo tablets, to avoididentification of the Placebo Group.

Physical examination a day before treatment start and on study days 7,14 and 30 includes body temperature (rectal), ocular system,musculoskeletal system, cardiovascular system, reproductive system,lymphatic system, behavior, nervous system, integumentary system,respiratory system, urinary system and gastro-intestinal system. Inaddition, blood and urine samples are analyzed before treatment andafter 30 days.

Repeated oral administration of imepitoin to clinically healthy male andfemale cats at high doses of 40 and 80 mg imepitoin/kg body weight twicedaily for 30 days is well tolerated by all cats, as none of the animalsdied prematurely and no considerable adverse events are observed.Behavioral changes or sedation is not noted during the course of thestudy. In this randomized, controlled, blinded study emesis isintermittently observed in the second and third week of treatment,indicating a transient effect at high doses. No hematological orbiochemical abnormalities are noted in the blood examination (see e.g.FIG. 3), and urine analysis shows physiological results.

Unexpectedly, imepitoin shows a favorable safety profile in felineanimals even at very high doses. In contrast to other antiepilepticdrugs, no severe sedation, severe and long lasting somnolence (i.e.longer than 3 hours), hepatotoxicosis, hepatic necrosis, liver failure,kidney damage, kidney failure, drug addiction, leukopenia,thrombocytopenia, lymphadenopathies, coagulopathies and/or death wasobserved.

Example 4—Efficacy 1

Most other known antiepileptics cause sedation in cats, which isespecially with phenobarbital quite pronounced. This is a severechallenge for the human-animal-interaction (pet owner/animal).

Two cats are diagnosed with epilepsy, having severe generalizedseizures. Both are treated with imepitoin at a starting dose of 30 mg/kgbodyweight twice daily.

The first cat, a 14 year old European Short-Hair cat, had two severegeneralized seizures. Both lasted around two minutes, the cat lostconsciousness and was disoriented after the seizure. In addition, afibrosarcoma and hyperthyroidism was diagnosed. The cat was treatedtwice a day with 100 mg imepitoin, being a dose of 25 mg/kg bodyweight.It responded immediately to treatment, showing no further seizures. Noconsiderable adverse events were observed. Initially, the cat showedtiredness 1-1.5 hours after application of the drug, which lasted forabout two hours. This resolved spontaneously after 10 days of treatment.After three months, the tiredness returned as described above, andconsequently the dose was reduced to 20 mg/kg bodyweight, and thetiredness disappeared. Until the end of the observation period of 6months, the cat did not show any seizures, demonstrating completeseizure freedom for 6 months.

The second cat, 7 years old, experienced two generalized seizures on twoconsecutive days, and the diagnosis was epilepsy of unknown cause. Thecat appeared to be sleepier in the time before occurrence of firstseizure. It also responded immediately to treatment with 30 mg/kgbodyweight imepitoin twice a day, but showed the tiredness observed inthe first cat already after treatment start. A reduction of the dose to10 mg/kg bodyweight twice daily resolved the tiredness, but with thisdose the cat experienced again a seizure. The dose was increased to 20mg/kg bodyweight imepitoin twice daily, and the cat showed completeseizure freedom for an observation period of 2.5 months. No tiredness orother adverse events were observed with this last dose.

Surprisingly and in contrast to dogs, a high dose of imepitoin leads toseizure freedom in cats with epilepsy, which is not achieved with lowdoses. Unexpectedly, no considerable adverse events were observed.

Example 5—Efficacy 2

Compared to untreated status at diagnosis, seizure frequency andseverity are significantly reduced—at least 40% of the cats even achieveseizure freedom when administering to feline patients a target dose ofe.g. 30 mg imepitoin/kg bodyweight twice daily at an interval of 8-14hours. Such cats do also not experience considerable adverse events. Inmost of the other cats, seizure frequency and severity are significantlyreduced.

In some animals, treatment with current standard of care, phenobarbital,is not effective and results in frequent severe seizures despitehigh-dose treatment. Administration of imepitoin in preferred doses,such as 20 to 60 mg/kg bodyweight, preferably such as 25 mg/kgbodyweight to 50 mg/kg bodyweight, more preferably such as 25 mg/kgbodyweight to 40 mg/kg bodyweight, two- or three-times daily reducesseizure frequency and/or severity significantly, in best case untilcomplete seizure freedom.

Example 6—Efficacy 3

Two groups of cats with epileptic disorders are treated with eitherimepitoin at a preferred dose of 30 mg/kg bodyweight twice daily or withphenobarbital at a common dose of 3.5 mg/kg bodyweight twice daily. Inthe phenobarbital group, 65% of treated cats experience at least oneadverse event, and approximately 40% of all treated cats experiencesedation as side effect. In contrast, the occurrence of adverse eventsis greatly and significantly reduced in the imepitoin treated groups,where about 30% of all cats experience at least on adverse event.

In the phenobarbital group, 30% of treated cats are considered poorlycontrolled and in 70% epilepsy was well controlled. For imepitoin, inabout 15% of cats treatment is not able to control the diseaseadequately. In 85% of cats seizures are well controlled, and themajority of them reach seizure freedom.

Example 7—Efficacy 4

Cats with epileptic disorders are treated with increasing doses ofphenobarbital, starting from 3 mg/kg bodyweight twice daily up to themaximum tolerated dose. With this treatment protocol, sustained andsignificant reduction in seizure frequency cannot be obtained, andseizures remain poorly controlled. According to this treatment failurethis represents drug-resistant epileptic disorders. The treatment ofthese cats with drug resistant epilepsy is now changed to imepitoin,provided at high doses as for example 30 mg/kg bodyweight twice daily.The seizure frequency of these cats reduced significantly by at least50% in most cases.

REFERENCES

-   (1) Barnes H L et al., JAVMA 2004, 225(11): 1723-1726-   (2) Bialer M et al., Epilepsy Research 1999, 34: 1-41-   (3) Bialer M et al., Epilepsy Research 2001, 43: 11-58-   (4) Bialer M et al., Epilepsy Research 2013, 103: 2-30-   (5) Boothe D M et al., JAVMA 2002, 221(8): 1131-1135-   (6) Fromm G H et al., Epilepsia 1985, 26(6): 672-681-   (7) Löscher W et al., Epilepsia 2004, 45(10): 1228-1239-   (8) Löscher W et al., Pharmacological Research 2013, 77: 39-46-   (9) Morimoto K et al., Epilepsia 1993, 34(6): 1123-1129-   (10) Pakozdy A et al., Journal of Feline Medicine and Surgery 2013,    15(4): 267-273-   (11) Pakozdy A et al., J Vet Intern Med 2014, 28(2):255-263-   (12) Penderis J et al., Veterinary Record 2013, 173: 323-324-   (13) Platt S R, Journal of the American Animal Hospital Association    2001, 37: 515-517-   (14) Quesnel A D et al., JAVMA 1997, 210(1): 72-77-   (15) Rieck S et al., The Veterinary Journal 2006, 172: 86-95-   (16) Rundfeldt C et al., CNS Drugs 2014, 28: 29-43-   (17) Schwartz-Porsche D et al., Feline Epilepsy. In: Inderi R J ed.    Problems in Veterinary Medicine. Vol. 1, No. 4., Philadelphia, Pa.,    Lippincott, 1989: 628-649-   (18) Smith Bailey K et al., Journal of Feline Medicine and Surgery    2009, 11: 385-394-   (19) WO 2004/032938-   (20) WO 2013/024023

The invention claimed is:
 1. A method for the treatment of one or moreepileptic disorders in a feline animal comprising administering to afeline animal suffering from said one or more epileptic disorders atherapeutically effective dose of1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof at a dose of 20 mg/kg bodyweightto 60 mg/kg bodyweight, wherein the dose is administered once, twice orthree times per day.
 2. A method for the prevention for up to twelvemonths of one or more epileptic disorders in a feline animal comprisingadministering to a feline animal suffering from said one or moreepileptic disorders a therapeutically effective dose of1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof at a dose of 20 mg/kg bodyweightto 60 mg/kg bodyweight, wherein the dose is administered once, twice orthree times per day.
 3. The method of treatment of claim 1, wherein theone or more epileptic disorders is selected from the group consisting ofidiopathic (primary, genetic) epilepsy, symptomatic (secondary,structural/metabolic) epilepsy, probable symptomatic (cryptogenic, ofunknown cause) epilepsy, and reactive epileptic seizures.
 4. The methodof treatment of claim 1, wherein1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof is administered in combinationwith one or more further antiepileptic drugs, in form of a simultaneous,a sequential and/or a chronologically staggered co-administration. 5.The method of treatment of claim 4, wherein the one or more furtherantiepileptic drug is selected from the group consisting of:phenobarbital, diazepam, potassium bromide, clorazepate, levetiracetam,gabapentin, zonisamide, pregabalin, propentophyllin, taurine,topiramate.
 6. The method of treatment of claim 1, wherein the one ormore epileptic disorders are antiepileptic drug resistant or -refractoryepileptic disorders.
 7. The method of treatment of claim 1, wherein1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof is administered as amonotherapy.
 8. The method of treatment of claim 1, wherein1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof is administered at a dose from25 to 40 mg/kg bodyweight, and wherein the dose is administered once,twice or three-times per day.
 9. The method of treatment of claim 1,wherein1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof is administered at a dose of 25to 40 mg/kg bodyweight, and wherein the dose is administered twice perday.
 10. The method of treatment of claim 1, wherein a highinitial/starting dose of1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one(imepitoin) or a physiologically acceptable salt thereof is reducedduring the course of treatment while maintaining one or more ofeffective control and/or prevention of seizures, moderate or goodseizure control, and complete prevention of seizures (seizure freedom)for a period up to twelve months, wherein the initial/starting dose isselected from the group consisting of from 20 to 60 mg/kg bodyweight,from 25 to 40 mg/kg bodyweight, 20 mg/kg bodyweight, 25 mg/kgbodyweight, 30 mg/kg bodyweight, 35 mg/kg bodyweight, 40 mg/kgbodyweight, 45 mg/kg bodyweight, 50 mg/kg bodyweight, 55 mg/kgbodyweight and 60 mg/kg bodyweight, and wherein the initial/startingdoes is reduced after initial treatment to lower maintenance dosesselected from the group consisting of from 0.5 to 60 mg/kg bodyweight,from 1 to 30 mg/kg bodyweight, from 5 to 20 mg/kg bodyweight, 1 mg/kgbodyweight, 2 mg/kg bodyweight, 5 mg/kg bodyweight, 8 mg/kg bodyweight,10 mg/kg bodyweight, 12.5 mg/kg bodyweight, 15 mg/kg bodyweight, 18mg/kg bodyweight, 20 mg/kg bodyweight, 22 mg/kg bodyweight, 25 mg/kgbodyweight and 30 mg/kg bodyweight, wherein all such doses areadministered once, twice or three-times per day.
 11. The method oftreatment according to claim 1, wherein1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof is administered orally orparenterally.
 12. The method of treatment according to claim 1, whereinthe administration of1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof leads to seizure freedom(complete prevention of seizures) in a given observation period of up to12 months, at doses selected from the group consisting of 20 to 60 mg/kgbodyweight, 25 to 40 mg/kg bodyweight, 20 mg/kg bodyweight, 25 mg/kgbodyweight, 30 mg/kg bodyweight, 35 mg/kg bodyweight, 40 mg/kgbodyweight, 45 mg/kg bodyweight, 50 mg/kg bodyweight, 55 mg/kgbodyweight and 60 mg/kg bodyweight.
 13. The method of treatmentaccording to claim 1, wherein the administration of1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one or aphysiologically acceptable salt thereof does not lead to considerableadverse events comprising one or more of severe sedation, severe andlong lasting somnolence, hepatotoxicosis, hepatic necrosis, liverfailure, kidney damage, kidney failure, drug addiction, leukopenia,thrombocytopenia, lymphadenopathies, coagulopathies and death.
 14. Themethod of treatment according to claim 1, wherein the feline animal is acat.
 15. The method of treatment according to claim 1, wherein the oneor more epileptic disorders are one or more of idiopathic (primary,genetic) epilepsy, symptomatic (secondary, structural/metabolic)epilepsy, and probable symptomatic (cryptogenic, of unknown cause)epilepsy.
 16. The method of treatment according to claim 1, wherein theone or more epileptic disorders are one or more ofphenobarbital-resistant or -refractory epileptic disorders,phenobarbital-resistant or -refractory idiopathic (primary, genetic)epilepsy, phenobarbital-resistant or -refractory symptomatic (secondary,structural/metabolic) epilepsy, and phenobarbital-resistant or-refractory probable symptomatic (cryptogenic, of unknown cause)epilepsy.